Several naturally-occurring alkaloids obtainable from Vinca rosea have been found active in the treatment of experimental malignancies in animals. Among these are leurosine (U.S. Pat. No. 3,370,057), vincaleukoblastine (vinblastine) to be referred to hereinafter as VLB (U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and leurocristine (VCR or vincrisitine) (both in U.S. Pat. No. 3,205,220), deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1958) desacetyl leurosine hydrazide is also disclosed therein); 4-desacetoxy vinblastine (U.S. Pat. No. 3,954,773; 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (U.S. Pat. No. 3,890,325) and vincadioline (U.S. Pat. No. 3,887,565). Two of these alkaloids, VLB and leurocristine, are now marketed as drugs for the treatment of neoplasms, VLB for the palliative treatment of lymphomas, generalized Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, mycosis fungoides, neuroblastoma, Letterer-Siwe disease, choriocarcinoma, carcinoma of the breast, and embryonal carcinoma of the testis. Vincristine is indicated in the treatment of acute leukemia, and in combination with other oncolytic agents, in Hodgkin's disease, lymphosarcoma, reticulum-cell sarcoma, rhabdomyosarcoma, neuroblastoma and Wilm's Tumor.
Chemical modification of the Vinca alkaloids has been rather limited. In the first place, the molecular structures involved are extremely complex and chemical reactions which affect a specific function of the molecule are difficult to develop. Secondly, alkaloids lacking desirable chemotherapeutic properties have been recovered from Vinca rosea fractions, and a determination of their structures has led to the conclusion that these compounds are closely related structurally to the antineoplastically-active alkaloids. Thus, antineoplastic activity seems to be limited to very specific structures, and the chances of obtaining more active drugs by modification of these structures would seem to be correspondingly slight. Among the successful modifications of physiologically-active alkaloids has been the preparation of dihydro VLB (U.S. Pat. No. 3,352,868) and the replacement of the acetyl group at C-4 (carbon no. 4 of the VLB ring system-see the numbered structure below) with higher alkanoyl group or with unrelated acyl groups. (See U.S. Pat. No. 3,392,173.) Several of these derivatives are capable of prolonging the life of mice inoculated with P1534 leukemia. One of the derivatives in which a chloracetyl group replaced the C-4 acetyl group of VLB was also a useful intermediate for the preparation of structurally modified VLB compounds in which an N,N-dialkylglycl group replaced the C-4 acetyl group of VLB (see U.S. Pat. No. 3,387,001). An intermediate compound, namely 4-desacetyl VLB, was produced during the chemical reactions leading to these latter derivatives. This intermediate, in which the C-4 acyl group was lacking, leaving an unesterified hydroxy group, has been reported to be a toxic material having little in vivo chemotherapeutic activity against the P1534 murine leukemia system by Hargrove, Lloydia, 27, 340 (1964).
A more recent modification has been the replacement of the ester group at C-3 with a carboxamide group. These novel amides are fully described in the parent of this application and in its predecessors--see also Belgian Pat. No. 347,275 issued 10-2-74 and Barnett et al., J. Med. Chem., 21, 88 (1978). One of these amides, 4-desacetyl VLB C-3 carboxamide, generic name vindesine, proposed trademark ELDISINE.RTM., is undergoing an extensive clinical trial in humans for treatment of acute lymphatic leukemia, acute granulocytic leukemia, chronic myeloid leukemia, non-small cell lung cancer, Hodgkin's disease, non-Hodgkin's lymphoma, malignant melanoma, carcinoma of the breast, esophageal carcinoma and testicular carcinoma.